The pathogenesis of Alzheimer?s disease (AD), the most common cause of dementia, is characterized by the accumulation of A? in the interstitial fluid (ISF) and its aggregation into soluble oligomers and insoluble amyloid plaques. This triggers a cascade of events including the formation of neurofibrillary tangles, neuronal dysfunction and degeneration, ultimately resulting in clinical dementia. In sporadic AD, age-dependent compromise of lysosome function in various brain cell types has been implicated in impaired A? metabolism, resulting in accelerated pathogenesis. Microglia, the primary immune cell in the brain phagocytose A? and amyloid plaques; but are observed to be engorged with residual amyloid material, suggesting impairment of lysosomal degradative capacity. Microglia are an isolated self-renewing population within the brain and peripheral monocytes do not cross the blood brain barrier under normal physiological conditions. Whether monocytes enter the AD brain is a current source of controversy. Our preliminary data with a fate-mapping strategy demonstrate that peripheral monocytes home in to amyloid plaques in aged APP/PS1 mice, a model of AD pathogenesis and take up amyloid material. Peripheral monocytes are more amenable to targeting via gene therapy or pharmacologic approaches than resident microglia and thus offer an opportunity to stimulate lysosomal function in cells that will target plaques within the brain parenchyma. We have demonstrated that exogenous expression of transcription factor EB (TFEB), a master inducer of lysosomal degradative pathways, stimulates lysosome biogenesis and function in astrocytes, to upregulate A? uptake via macropinocytosis and accelerate its lysosomal degradation resulting in attenuated amyloid plaques. Whether targeting TFEB to resident microglia or circulating monocytes facilitates amyloid phagocytosis and lysosomal degradation to attenuate plaque pathogenesis and improve neuronal function, needs to be explored. Hypothesis: Ontogeny-based targeting of exogenous TFEB to microglia and peripheral monocytes is sufficient to stimulate amyloid uptake and degradation; and attenuate amyloid plaques and neuronal pathology in AD. To test this hypothesis, we propose three specific aims: SA1: Determine if enhancing lysosomal function with TFEB expression in microglia attenuates plaque pathogenesis in AD mouse models. SA2: Examine the role of peripheral monocyte recruitment in amyloid plaque pathogenesis. SA3: Determine if enhancing TFEB expression specifically in circulating monocytes affects monocyte recruitment and plaque pathogenesis in AD mouse models.